Proteasomes and Antigen Processing

Tanaka, K.; Tanahashi, Nobuyuki; Tsurumi, Chizuko; Yokota, K; Shimbara, Naoki

doi:10.1016/s0065-2776(08)60885-8

Cited by 107 publications

(80 citation statements)

References 120 publications

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“…Recently PA28 has been implicated as a regulator of immune function (Tanaka et al 1997). Intriguingly, PA28a (equivalent to the originally described PA28/ 11S regulator) is identical to IGUP I-5111, which is one of the major gene products induced by g-IFN in primary human keratinocytes (Honoré et al 1993).…”

Section: Discussionmentioning

confidence: 98%

“…Previously, we (Akiyama et al 1994;Hisamatsu et al 1996) and others (Belich et al 1994;Früh et al 1994) suggested that g-IFN may induce replacements of the three proteasome subunits X (MB1), Y (delta), and Z, by very homologous, but different, subunits named LMP7, LMP2 and MECL1, respectively, producing proteasomes that are perhaps responsible for the immunological processing of endogenous antigens. Therefore we propose the term 'immunoproteasomes' to indicate distinct proteasomes induced by g-IFN (Tanaka et al 1997). This idea is based on the findings that g-IFN induced not only a marked increase in both mRNA and protein levels of LMP7, LMP2 and MECL1, but also almost complete loss of the proteins X, Y and Z without affecting their mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

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Molecular properties of the proteasome activator PA28 family proteins and γ‐interferon regulation

et al. 1997

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Background: Recent cDNA cloning of two homologous proteasome activators, PA28a and PA28b, indicated the presence of a structurally related third protein, Ki antigen, but a functional relationship between Ki antigen and the two PA28 proteins is unknown. Accumulating evidence has implicated an important role for PA28 in the major histocompatibility complex (MHC) class I-restricted antigen processing pathway. Recently, an immunomodulatory cytokine g-interferon (g-IFN) was found to increase greatly the messages for PA28a and PA28b, but not Ki antigen, in human cells.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Molecular properties of the proteasome activator PA28 family proteins and γ‐interferon regulation

et al. 1997

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“…It is known that two MHC-encoded proteasomal subunits, LMP2 and LMP7, have a polymorphism, but so far there has been no evidence which has indicated a relationship between their polymorphic nature and catalytic mode (Monaco & Nandai 1995). Moreover, 'immunoproteasomes' containing interferon-g inducible subunits such as LMP2, LMP7 and MECL1, are found to alter their cleavage specificity to produce efficiently immunodominant MHC class I ligands (York & Rock 1996;Groettrup et al 1996a;Tanaka et al 1997). This seems to be an adaptive change which was acquired during vertebrate evolution to accelerate the immune response, and differs from species specificity.…”

Section: Discussionmentioning

confidence: 99%

“…The major target proteins degraded by this enzyme must first be modified by covalent conjugation to a polyubiqutin chain as a degradation signal (Hochstrasser 1997). The ubiquitin-proteasome system has been implicated as a processing enzyme, generating immunodominant MHC ligands from endogenous antigens (Monaco & Nandai 1995;Groettrup et al 1996a;Tanaka et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Double‐cleavage production of the CTL epitope by proteasomes and PA28: role of the flanking region

et al. 1997

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Background: Proteasomes are known to produce major histocompatibility complex (MHC) class I ligands from endogenous antigens, and the ginterferon-inducible proteasome activator PA28 has been thought to play an important role in the generation of immunodominant MHC ligands by proteasomes. Several attempts have been made to show that proteasomes have the ability to yield cytotoxic T lymphocyte (CTL) epitopes effectively from model polypeptides derived from viral and intracellular proteins in vitro, but their antigen processing mechanism is poorly understood.

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“…Ubiquitinmediated proteolysis is also required at many stages in the cell cycle (20) and in the elimination of specific proteins during DNA repair (21,22). Indeed, ubiquitin-mediated proteolysis has been implicated in processes as diverse as antigen presentation on major histocompatibility complex class I molecules (23)(24)(25) and proper telomere behavior during cell division (26). Discovering how polyubiquitin chains are recognized by the 26 S protease is central to understanding a number of regulatory mechanisms.…”

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confidence: 99%

Characterization of Two Polyubiquitin Binding Sites in the 26 S Protease Subunit 5a

Young¹,

Deveraux²,

Beal³

et al. 1998

Journal of Biological Chemistry

290

267

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Ubiquitylated proteins are degraded by the 26 S protease, an enzyme complex that contains 30 or more unique subunits. One of these proteins, subunit 5a (S5a), has been shown to bind ubiquitin-lysozyme conjugates and free polyubiquitin chains. Using deletional analysis, we have identified in the carboxyl-terminal half of human S5a, two independent polyubiquitin binding sites whose sequences are highly conserved among higher eukaryotic S5a homologs. The sites are approximately 30-amino acids long and are separated by 50 intervening residues. When expressed as small fragments or when present in full-length S5a molecules, the sites differ at least 10-fold in their apparent affinity for polyubiquitin chains. Each binding site contains 5 hydrophobic residues that form an alternating pattern of large and small side chains, e.g. Leu-Ala-Leu-Ala-Leu, and this pattern is essential for binding ubiquitin chains. Based on the importance of the alternating hydrophobic residues in the binding sites and previous studies showing that a hydrophobic patch on the surface of ubiquitin is essential for proteolytic targeting, we propose a model for molecular recognition of polyubiquitin chains by S5a.Ubiquitin is a small, highly conserved eukaryotic protein that can be covalently attached to a variety of cellular proteins including itself (1). Ubiquitylation requires an activating enzyme E1, Ub 1 carrier proteins E2s, and substrate recognition components called E3s (2, 3). Post-translational modification of proteins by ubiquitin may serve several functions. Addition of monomers of ubiquitin to histones or insect actin appears to affect the higher order structure of chromatin or flight muscle, respectively (4, 5). More recently, ubiquitylation has been implicated in endocytosis of the Ste2p yeast mating type receptor (6), and ubiquitin has been proposed to serve a novel nonproteolytic role in the regulated activation of I␤␣ kinase (7). However, the best characterized function of ubiquitin is to promote the degradation of proteins to which it is attached especially when substrates are bound to a polyubiquitin chain rather than individual ubiquitin moieties (8). Polyubiquitin chains are formed by isopeptide linkages involving the C-terminal glycine (Gly 76 ) of one ubiquitin and a lysine ⑀ amino group on another. A ␤-galactosidase fusion protein covalently attached to a polyubiquitin chain consisting of 8 -12 ubiquitins linked by Gly 76 -Lys 48 isopeptide bonds is degraded approximately 10 times more rapidly than the monoubiquitylated substrate (8).The 26 S protease, which was discovered by its ability to degrade ubiquitin-lysozyme conjugates (9), is now known to be formed from two particles, the 19 S regulatory complex (10 -13) and the 20 S proteasome (14, 15). The regulatory complex confers substrate recognition and energy dependence upon the 26 S enzyme, and the proteasome provides proteolytic activities. Although the 26 S protease has been shown to degrade native unmodified ornithine decarboxylase (16), this enzyme of polyamine metab...

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Proteasomes and Antigen Processing

Cited by 107 publications

References 120 publications

Molecular properties of the proteasome activator PA28 family proteins and γ‐interferon regulation

Molecular properties of the proteasome activator PA28 family proteins and γ‐interferon regulation

Double‐cleavage production of the CTL epitope by proteasomes and PA28: role of the flanking region

Characterization of Two Polyubiquitin Binding Sites in the 26 S Protease Subunit 5a

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